Early Downward Trends in Neurodevelopmental Disorders Following Removal of Thimerosal-Containing Vaccines

David A. Geier, B.A. Thimerosal is an ethylmercury-containing compound (49.6% Mark R. Geier, M.D., Ph.D. mercury by weight) that was historically added to many vaccines at the preservative level (0.005% to 0.01%). The U.S. Centers for Disease Control and Prevention (CDC), from the late 1980s ABSTRACT through the 1990s, expanded the number of doses of TCVs to be administered to U.S. infants. To five doses of diptheria-tetanus- Contemporaneously with the epidemic rise in neuro- developmental disorders (NDs), first observed in the United States whole-cell-pertussis (DTP) vaccine were added three doses of during the 1990s, the childhood immunization schedule was hepatitis B (Hep b) vaccine and four of Haemophilus influenzae expanded by the U.S. Centers for Disease Control and Prevention type b (Hib) vaccine. Additionally, the CDC began recommending (CDC) to include several additional thimerosal-containing vaccines three doses of influenza vaccine for certain infant populations. An (TCVs). On July 7, 1999, a joint recommendation was made by the infant who received all of these vaccines on schedule could have American Academy of Pediatrics (AAP) and the U.S. Public Health received as much as 200 micrograms (µg) of mercury during the Service (PHS) to remove thimerosal from vaccines. A two-phase first 6 months of life.14 study was undertaken to evaluate trends in diagnosis of new NDs In response to theoretical concerns about the cumulative doses entered into the Vaccine Adverse Event Reporting System of mercury from TCVs, theAAPand the U.S. Public Health Service (VAERS) and the California Department of Developmental Services (PHS) issued a joint statement on July 7, 1999, calling for the (CDDS) databases on a reporting quarter basis, from 1994 through removal of thimerosal from all vaccines.14 It has been estimated that 2005. Significant increasing trends in newly diagnosed NDs were the last thimerosal-containing Hep b, diphtheria-tetanus-acellular- observed in both databases 1994 through mid-2002. Significant pertussis (DTaP) and Hib vaccines were manufactured in 2000- decreasing trends in newly diagnosed NDs were observed in both 14 databases from mid-2002 through 2005. The results indicate that 2001 and expired at the end of 2002 (or early 2003). Table 1 the trends in newly diagnosed NDs correspond directly to the summarizes significant historical dates in the use of pediatric TCVs expansion and subsequent contraction of the cumulative mercury in the United States. dose to which children were exposed from TCVs through the U.S. Considering all significant environmental exposures to immunization schedule. mercury, such as through breast milk, TCVs represent almost 50% of the total mercury dose some infants received.15 The 187.5 µg of Background mercury through TCVs plus the average of 164 µg from breast milk during the first 6 months exceeded the methylmercury safety In 2004, the Department of Health and Human Services and guidelines established by the U.S. Environmental Protection the American Academy of Pediatrics (AAP) issued an Autism Agency (EPA), Health Canada, the World Health Organization A.L.A.R.M., stating that 1 in 166 children currently have an (WHO), the Agency for Toxic Substances Disease Registry 15 autistic disorder, and 1 in 6 children have a developmental and/or (ATSDR), and the U.S. Food and Drug Administration (FDA). behavioral disorder. Autism, once rare, is now more prevalent With no additional exposure from any source, these doses also 1 exceeded the methylmercury guidelines for the first year of life set than childhood cancer, diabetes, and Down syndrome. Epidemic 15 trends in neurodevelopmental disorders (NDs) were first by all of these agencies except the FDA. observed in the United States during the 1990s,1-8 and cannot be Despite its removal from many childhood vaccines, thimerosal explained by immigration, changed diagnostic criteria, or is still routinely added to some formulations of influenza vaccine administered to U.S. infants, as well as to several other vaccines improved identification.1, 6-8 (e.g. tetanus-diphtheria and monovalent tetanus) administered to Autism is an ND characterized by impairments in social older children and adults. In 2004, the Institute of Medicine (IOM) relatedness and communication, repetitive behaviors, and 1 of the U.S. NationalAcademy of Sciences (NAS) retreated from the stereotypic abnormal movements. While genetic factors are stated 1999 goal of theAAPand the PHS to remove thimerosal from important in the pathogenesis of autistic disorders, a role for U.S. vaccines as soon as possible.16 Furthermore, many nations still environmental factors has received considerable attention. add thimerosal to many of their pediatric vaccines, and WHO and Exposure to mercury has previously been shown to cause several vaccine manufacturers still advocate the continued use of immune, sensory, neurological, motor, and behavioral thimerosal in pediatric vaccines. As a result, assessing the safety of dysfunctions similar to traits defining or associated with autistic TCVs is a matter of significant importance. disorders, and with similarities in neuroanatomy, neuro- Examinations of the VaccineAdverse Event Reporting System transmitters, and biochemistry.9-12 Furthermore, recent research that (VAERS), the U.S. Department of Education, and the Vaccine codes children’s communicative, social, affective, repetitive Safety Datalink (VSD) databases showed significant links between behaviors, and toy play from videotapes of the toddlers’ first and exposure to TCVs and NDs.17-23 Specifically, data from VAERS second birthday parties demonstrates that the regression associated showed that additional doses of mercury from thimerosal- with autistic disorders clearly manifests between the ages of 12 and containing DTaP in comparison to thimerosal-free DTaP 24 months,13 concurrent with the exposure to thimerosal-containing (administered in the late 1990s), and additional doses of childhood vaccines (TCVs). thimerosal-containing DTP and Hib in comparison to diphtheria-

8 Journal of American Physicians and Surgeons Volume 11 Number 1 Spring 2006 Table 1. Significant Dates Regarding the Use of Thimerosal in U.S. Pediatric Vaccines Date Significant Events Middle 1980s Thimerosal is present in virtually all whole-cell diphtheria-tetanus-whole-cell-pertussis (DTP) vaccines administered to children four times, starting at age 2 mon, during the first 18 mon of life (maximum of 25 µg Hg/dose). Maximum Hg exposure in 18 mon: 100 µg.

Late 1980s Thimerosal-containingHaemophilus influenzae type b (Hib) vaccine is administered to children at age 18 mon (maximum of 25 µg Hg/dose). Maximum Hg exposure in 18 mon: 125 µg.

Early 1990s Four doses of thimerosal-containing Hib are recommended within 18 months, starting at age 2 mon (maximum of 25 µg Hg/dose). Maximum Hg exposure in 18 mon: 200 µg.

Early 1990s Three doses of thimerosal-containing hepatitis B (Hep b) vaccine are recommended within the first 6 mon, starting on the day of birth (maximum of 12.5 µg Hg/dose). Maximum Hg exposure in 18 mon: 237.5 µg.

Middle 1990s Some DTP and Hib vaccines are combined to produce DTPH vaccine, which has only 25 µg of mercury per immunization, reducing mercury levels of exposure for some children, but is rapidly replaced by diphtheria-tetanus-acellular-pertussis (DTaP) vaccines beginning in 1996 (DTaPvaccine is almost exclusively produced separately from Hib vaccine).

1996-1997 GlaxoSmithKline introduces a new thimerosal-free DTaP vaccine (Infarix) that contains 2-phenoxethanol as a preservative. Aventis Pasteur introduces a new Hib vaccine (ActHIB) that contains no preservative.

Late 1990s Three doses of thimerosal-containing influenza vaccine are increasingly recommended for administration to children during the first 18 mon, starting at age 6 mon (12.5 µg Hg/dose). Maximum Hg exposure: 200 µg in first 6 mon and 275 µg in first 18 mon.

July 7, 1999 AAP and PHS request removal of thimerosal from all pediatric vaccines as rapidly as possible, and AAP suggests delaying Hep b vaccine until after age 6 mon for children born to hepatitis B negative mothers.

August 27, 1999** Thimerosal-free Recombivax HB (Merck) is licensed by the FDA.

March 28, 2000 Thimerosal-free Engerix-B (GlaxoSmithKline) is licensed by the FDA.

March 7, 2001 Thimerosal-free Tripedia (Aventis Pasteur) is licensed by the FDA.

Late 2002/ CDC and FDA claim that the last remaining doses of thimerosal-containing DTaP, Hep b, or Hib vaccines are administered to U.S. Early 2003 children. ** Thimerosal-containing formulations continued to be distributed/administered following FDA licensing of thimerosal-free formulations. tetanus-pertussis-Haemophilus influenzae type b (DTPH) vaccines adverse events following vaccination are required by law to be (ad-ministered in the early to mid-1990s), were associated with a reported to this database. The VAERS Working Group of the CDC significant 2- to 8-fold increase in risk of NDs, depending upon the has previously reported that less than 5% of the reports come from symptoms or outcomes examined. The one other U.S. parents. The VAERS Working Group and the FDA analyze and epidemiological study that has examined the relationship between publish epidemiologic studies based upon analyses of VAERS. TCVs and NDs, by Verstaeten et al. from the CDC, initially found a They note that VAERS is simple to use, flexible by design, and significant relationship between TCVs and some types of provides data in a timely fashion, but warn that the potential neurodevelopmental disorders (NDs), but upon examining a 24 limitations may include systematic error due to underreporting, different dataset, it did not find a consistent effect. The lead author erroneous reporting, frequent multiple exposures, multiple concluded that this study could neither accept nor reject a causal outcomes, and lack of precise denominators.26 relationship between TCVs and NDs.25 Analysis Methods: The online public access VAERS database Now that a number of children have received reduced doses of (updated through August 31, 2005) was examined using Microsoft mercury from TCVs for several years, the present rapid sampling Access.27 The entire database was surveyed for duplicate reports study was undertaken to check for an effect on the occurrence of (i.e. those having the same VAERS ID number), and these were NDs. The first phase consisted of an evaluation of newly eliminated. An ecological method was employed to evaluate NDs diagnosed NDs received by VAERS. The second phase examined reported following immunizations, including autism (Costart Term whether the VAERS observations were consistent with trends in = Autism) and speech disorders (Costart Term = Speech Dis), the new autism reports in the California Department of among children< 5 years old). Descriptions of these adverse events Developmental Services (CDDS). by those reporting them were coded by VAERS technical staff into defined symptom fields. The total new number of adverse event Materials and Methods reports for each type of ND received on a reporting-quarter basis (January through March, April through June, July through Phase I: The VaccineAdverse Events Reporting System September, and October through December) for 36 consecutive The VAERS database has been maintained by the CDC since reporting quarters, from January 1, 1994, through December 31, 1990 as a surveillance tool to evaluate vaccine safety. Specific 2002, and for 14 consecutive reporting quarters from January 1,

Journal of American Physicians and Surgeons Volume 11 Number 1 Spring 2006 9 Table 2. Regression Equations for the VAERS and CDDS Databases.

2002, through June 30, 2005, were evaluated in VAERS. The Analysis Methods: The online public access CDDS database reporting quarter periods were defined so as to overlap slightly, to (updated through October 4, 2005) was examined using Microsoft maximize the possibility of capturing the peak reporting period in Access.1,28 The total new number of autism reports received by the both groups. Assuming a 3- to 4- year lag time between birth and CDDS from 36 consecutive reporting quarters (from that starting diagnosis of an ND,24 the peak followed by a decline in NDs would on January 24, 1994, through that ending on January 6, 2003), and be expected to occur around 2002 if thimerosal had a significant for 15 consecutive reporting quarters (from that starting on January impact on NDs. 3, 2002, through that ending on October 4, 2005) were analyzed. These periods of examination in the CDDS database were selected Phase II : California Department of Developmental Services in an attempt to mirror the VAERSreporting periods analyzed in the The California regional center system consists of 21 nonprofit present study. and independent agencies, which are under contract with the The simple linear regression test in the StatsDirect (Version Department of Developmental Services to provide services to 2.4.2) statistical package was used to determine the equations for persons with developmental disabilities. The CDDS system was the regression lines, the slope of the regression lines, the correlation 2 created in 1969. Originally, autism was not included in the coefficients (r), the regression coefficients (R ), andP -values for the number of newly diagnosed NDs reported to VAERS and Lanterman Developmental Disabilities Services Act that CDDS during the two time periods before and after removal of established the statewide system of services. Autism, a low- thimerosal. The null hypothesis was that the slope of the lines for incidence disorder in 1969, was added in 1971, largely because the each of the two periods would be equal to zero. Additionally, the impact of autism on children was substantially disabling and data were examined using the Kruskal-Wallis test statistic to expected to be a lifelong condition. The CDDS recognizes only determine whether the introduction, followed by removal, of professionally diagnosed individuals with mental retardation, thimerosal from childhood vaccines produced a discernable trend autism, epilepsy, cerebral palsy, and conditions similar to mental in the two separate reporting quarter periods examined in the retardation as conditions eligible for services. Persons diagnosed VAERS and the CDDS databases. The null hypothesis was that the with one of the other Pervasive Developmental Disorders (PDD), total number of newly diagnosed NDs should not be affected by the including Pervasive Developmental Disorder, Not Otherwise introduction/removal of thimerosal from childhood vaccines; in Specified (PDD, NOS), Asperger’s Disorder, Rett’s Disorder, and other words, that the slope of the lines for the two periods would be Childhood Disintegrative Disorder are not eligible for regional the same. A two-sidedP -value of < 0.05 was considered center services.1 statistically significant.

10 Journal of American Physicians and Surgeons Volume 11 Number 1 Spring 2006 P

P

P

Figure 1. Trends in New Autism Adverse Events Reported to VAERS. The Figure 2. Trends in New Cases of Speech Disorders Reported to VAERS. trend from Jan 1, 1994, through Dec 31, 2002, is significantly increasing, The trend from Jan 1, 1994, through Dec 31, 2002, is significantly withP < 0.0001. The trend from Jan 1, 2002, through June 30, 2005, is increasing, withP < 0.0001. The trend from Jan 1, 2002, through June 30, significantly decreasing, withP < 0.02. The difference in the slope of the 2005, is significantly decreasing, withP < 0.03. The difference in the slope of regression lines for the number of new autism adverse events in the earlier the regression lines for the number of new speech disorder adverse events compared with the later periods is significant, withP < 0.0005. in the earlier compared with the later periods is significant, withP < 0.005.

Results containing DTP vaccine, starting at 2 months of age. Subsequently, the children who were entered into the VAERS and CDDS Figures 1 and 2 show the trend for new cases of autism and databases from early 1994 through mid-to-late 2002 were probably speech disorder (among those< 5 years old) reported to VAERSfor born from the late 1980s to early 1990s through the late 1990s. the 36 consecutive reporting quarters from January 1994 through These children, as shown in Table 1, received increasing doses of December 2002, compared with that for 14 consecutive reporting mercury from additional TCVs (Hib, Hep b, and in some cases quarters from January 2002 through June 2005. There was a influenza) as they were added to the recommended immunization significant difference in the trends, from an increasing to a schedule. Peak exposure from TCVs during the first 18 months of decreasing slope, (PP < 0.0005 for autism and < 0.005 for speech life was 275 µg mercury. Lastly, children entered into the VAERS disorder). and CDDS databases in the last period, beginning in mid-2002, Figure 3 evaluates the trend of new cases of autism entered into were probably born from the late 1990s through the early 2000s. the CDDS for the 36 consecutive reporting quarters from January Table 1 shows that after July 7, 1999, as thimerosal was removed 24, 1994, through January 6, 2003, and for the 15 consecutive from vaccines, the total mercury dose children received from TCVs reporting quarters from January 3, 2002, through October 4, 2005. was gradually reduced, and what mercury remained in childhood For new cases of autism, the trends were significantly different (P < vaccines was administered in a significantly less rigorous schedule 0.0001). About 350 fewer cases of autism were reported to the than in previous time periods. Overall, it appears that the increasing CDDS in the reporting quarter ending on October 4, 2005, than and subsequent decreasing trends in the rates of NDs, observed in would have been expected from extrapolating the trend line for the both the VAERS and CDDS databases, correlate with temporal first set of 36 reporting quarters. About 200 fewer new cases of periods when the cumulative amount of mercury in the childhood autism were reported to the CDDS in the last reporting quarter of immunization schedule expanded and later contracted. the second set of 15 consecutive quarters than in the first of that set. The consistency of the effects observed for the spectrum of Table 2 summarizes the equations of the regression lines, the NDs, including autism and speech disorders, and the agreement slope of the regression lines, the correlation coefficients, the between the observations from two separate databases, support the regression coefficients,P -values, and 95% confidence intervals conclusion that the effect is real and not a chance observation. The (CIs) in the present study. magnitude of the change in the trend lines is substantial. Moreover, other data are confirmatory: provisional data from the U.S. Discussion Department of Education show a recent decrease of 529 in the number of new autism diagnoses recorded among children 3 to 5 In the present study a novel rapid sampling epidemiologic years old, after years of annual increases. There were 1,451 new technique was employed to evaluate trends in new NDs entered into cases in 2001-2002; 1,981 in 2002-2003; 3,707 in 2003-2004; and two separate databases, the VAERSand the CDDS. It was observed 3,178 in 2004-2005.29 that consistent significant trends were found in both databases, with The biological plausibility of the present findings is further limited effects from systematic error/bias. supported by recently emerging extensive toxicokinetic, There is a median lag time of 3 to 4 years between the time of molecular, and animal studies. birth and the diagnosis of an ND.24 As a result, the first children Burbacher et al. have evaluated infant monkeys following evaluated, whose reports were entered into the VAERS and CDDS injection of doses of mercury comparable to the dosing schedule databases in early 1994, were probably born in the late 1980s or (weight- and age-adjusted) that U.S. children received during the early 1990s.As was summarized in Table 1, these children received 1990s.30 These researchers confirmed that thimerosal crosses the approximately 100 µg mercury from four doses of thimerosal- blood-brain barrier and results in appreciable mercury content in

Journal of American Physicians and Surgeons Volume 11 Number 1 Spring 2006 11 urinary mercury concentration following chelation. Holmes et al. examined first baby haircuts and determined that autistics had significantly higher body burdens of mercury in comparison to nonautistic matched controls, by demonstrating that the mercury level in hair, and thus the ability to excrete mercury, was inversely proportional to the severity of autism and overall much lower in the 49 P autistic group. James et al. have evaluated biochemical susceptibility to mercury in autistic children, in comparison to age- and gender-matched control children, by evaluating the methionine P cycle and transsulfuration metabolites. They found a significant 46% decrease in the plasma concentration of glutathione, a necessary metabolite for the excretion of mercury from the body. Additionally, autistic children had significantly increased oxidative stress, as shown by a three-fold decrease in the glutathione/oxidized glutathione redox ratio, in comparison to control children, which would correlate with a significant body burden of mercury.50-53 Figure 3. Trends in New Cases of Autism Entered into the CDDS. The trend from Jan 24, 1994, through Jan 6, 2003, is significantly increasing, withP < 0.0001. The trend from Jan 6, 2002, through Oct 4, 2005, is significantly Conclusions decreasing, withP < 0.05. The difference in the slope of the regression lines for the number of new autism cases in the earlier compared with the later The present controlled assessment of VAERS and CDDS periods is significant, withP < 0.0001. databases shows that very specific NDs are associated with TCVs. This conflicts with the 2004 conclusions of the IOM, largely based upon examination of vaccine safety data from the National tissues including the brain. They determined that the overall half- Immunization Program (NIP) of the CDC. The IOM stated that the life of mercury in the brain of the infant monkeys examined was evidence favored rejection of a causal relationship between approximately 24 days. In addition, it was determined that the thimerosal and autism, that such a relationship was not concentration of inorganic mercury in the brains of the biologically plausible, and that no further studies should be thimerosal-treated infant monkeys averaged 16 ppb following the conducted to evaluate it.16 dosing schedule, and the half-life of this inorganic mercury was From data presented here and other emerging data, it appears very long (> 120 days). clear that additional research should be undertaken concerning the In a series of in vitro studies with neurons it has now been shown effects of mercury exposure, particularly from TCVs. This is that nanomolar (nM) to micromolar (µM) concentrations of especially true in light of the fact that the handling of vaccine safety thimerosal are capable of inducing neuronal death, data by the NIPhas recently been called into question by the IOM.54 neurodegeneration, membrane damage, and DNA damage within hours of exposure.31-38 Additionally, it has been shown that nM to David A. Geier, B.A., is a graduate student in biochemistry, George Washington University.Mark R. Geier, M.D., Ph.D. is President, the Genetic µM concentrations of thimerosal are capable of disrupting critical Centers of America. Contact: Dr. Mark Geier at 14 Redgate Ct., Silver Spring, signaling pathways and biochemical events necessary for neurons MD 20905. Telephone: (301) 989-0548, fax (301) 989-1543. E-mail: to undergo normal development.39-41 Such disruptions include [email protected]. testosterone-mercury synergistic induced neurotoxicity, while 42,43 Acknowledgements: We wish to thank Lisa Sykes for helping to revise and estrogen significantly reduced mercury-induced neurotoxicity. edit our manuscript. Hornig et al. administered thimerosal to mice, mimicking the U.S. routine childhood immunization schedule of the 1990s Potential conflict of interest: David Geier has been a consultant in (weight- and age-adjusted), and observed autistic symptoms in a vaccine/biologic cases before the no-fault National Vaccine Injury Compensation Program (NVICP) and in civil litigation. Dr. Mark Geier has susceptible mouse strain that included growth delay, reduced been an expert witness and a consultant in vaccine/biologic cases before locomotion, exaggerated response to novelty, increased brain size, the no-fault NVICP and in civil litigation. decreased numbers of Purkinje cells, significant abnormalities in brain architecture affecting areas subserving emotion and REFERENCES 1 California Department of Developmental Services. Autistic Spectrum cognition, and densely packed hyperchromic hippocampal neurons Disorders Changes in the California Caseload An Update: 1999 44 with altered glutamate receptors and transporters. In addition, through 2002. Sacramento, Calif.: State of California; 2003. thimerosal exposure at specific prenatal developmental stages in 2 Gerlai R, Gerlai J. Autism: a target for pharmacotherapies? 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